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PMID:8573071

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Citation

Si-Tahar, M, Renesto, P, Falet, H, Rendu, F and Chignard, M (1996) The phospholipase C/protein kinase C pathway is involved in cathepsin G-induced human platelet activation: comparison with thrombin. Biochem. J. 313 ( Pt 2):401-8

Abstract

Cathepsin G, an enzyme released by stimulated polymorphonuclear neutrophils, and thrombin are two human proteinases which potently trigger platelet activation. Unlike thrombin, the mechanisms by which cathepsin G initiates platelet activation have yet to be elucidated. The involvement of the phospholipase C (PLC)/protein kinase C (PKC) pathway in cathepsin G-induced activation was investigated and compared with stimulation by thrombin. Exposure of 5-[14C]hydroxytryptamine-labelled platelets to cathepsin G, in the presence of acetylsalicylic acid and phosphocreatine/creatine kinase, induced platelet aggregation and degranulation in a concentration-dependent manner (0.1-3.0 microM). Time-course studies (0-180 s) comparing equivalent concentrations of cathepsin G (3 microM) and thrombin (0.5 unit/ml) resulted in very similar transient hydrolysis of phosphatidylinositol 4,5-bisphosphate and steady accumulation of phosphatidic acid. In addition cathepsin G, like thrombin, initiated the production of inositol phosphates. The neutrophil-derived proteinase also induced phosphorylation of both the myosin light chain and pleckstrin, a substrate for PKC, to levels similar to those observed in platelets challenged with thrombin. Inhibition of PKC by GF 109203X, a specific inhibitor, suppressed platelet aggregation and degranulation to the same extent for both proteinases. Using fura 2-loaded platelets, the rise in the cytosolic free Ca2+ concentration induced by cathepsin G was shown to result, as for thrombin, from both mobilization of internal stores and Ca2+ entry across the plasma membrane. These findings provide evidence that cathepsin G stimulates the PLC/PKC pathway as potently as does thrombin, independently of thromboxane A2 formation and ADP release, and that this pathway is required for platelet functional responses.

Links

PubMed PMC1216922

Keywords

Amino Acid Sequence; Blood Platelets/metabolism; Calcium/metabolism; Cathepsin G; Cathepsins/physiology; Enzyme Activation; Humans; Molecular Sequence Data; Phospholipids/metabolism; Phosphorylation; Platelet Activation/physiology; Protein Kinase C/metabolism; Serine Endopeptidases; Serotonin/metabolism; Thrombin/physiology; Type C Phospholipases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CATG

GO:0006468: protein phosphorylation

ECO:0000314:

P

Figure 4 Time course of protein phosphorylation in platelets challenged with cathepsin G or thrombin.

complete
CACAO 6088

HUMAN:CATG

GO:0030168: platelet activation

ECO:0000314:

P

Fig 1,2. Figure 5 Effect of GF 109203X on platelet activation induced by cathepsin G or thrombin.

complete
CACAO 6089

HUMAN:CATG

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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